High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma

• Published in: PloS one Vol. 8; no. 2; p. e56827
• Main Authors: Bancos, Irina, Bida, John Paul, Tian, Defeng, Bundrick, Mary, John, Kristen, Holte, Molly Nelson, Her, Yeng F, Evans, Debra, Saenz, Dyana T, Poeschla, Eric M, Hook, Derek, Georg, Gunda, Maher, 3rd, L James
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.02.2013; Public Library of Science (PLoS)
• Subjects: Alcohol dehydrogenase; Alcoholism; Alcohols; Analysis; Baking yeast; Biochemistry; Biology; Cancer; Cancer genetics; Cell death; Cells (Biology); Chemotherapy; Defects; Dehydrogenase; Dehydrogenases; Disulfiram; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - pharmacology; Galactose - metabolism; Genes; Genetic aspects; Genomes; Glucose metabolism; Glycolysis; Growth; Growth Inhibitors - pharmacology; High-throughput screening; Inhibitors; Kinases; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - antagonists & inhibitors; Lactate dehydrogenase; Lactic acid; Medical screening; Medicine; Metabolism; Models, Theoretical; Molecular biology; Mutation; NAD; Neuroendocrine tumors; Paraganglioma; Paraganglioma - enzymology; Pharmacy; Physiological aspects; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Succinate dehydrogenase; Succinate Dehydrogenase - genetics; Tricarboxylic acid cycle; Tumor suppressor genes; Tumorigenesis; Tumors; Yeast; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056827

Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.